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e PREFACET he Milestones in Science and Discovery set is based on a simple but powerful idea—that science and technology are not sepa-rate from people’s daily lives. Rather, they are part of seeking tounderstand and reshape the world, an activity that virtually definesbeing human. More than a million years ago, the ancestors of modern humansbegan to shape stones into tools that helped them compete with thespecialized predators around them. Starting about 35,000 yearsago, the modern type of human, Homo sapiens, also created elabo-rate cave paintings and finely crafted art objects, showing that tech-nology had been joined with imagination and language to composea new and vibrant world of culture. Humans were not only shapingtheir world but representing it in art and thinking about its natureand meaning. Technology is a basic part of that culture. The mythologies ofmany peoples include a trickster figure, who upsets the settledorder of things and brings forth new creative and destructive pos-sibilities. In many myths, for instance, a trickster such as the NativeAmericans’ Coyote or Raven steals fire from the gods and gives itto human beings. All technology, whether it harnesses fire, electric-ity, or the energy locked in the heart of atoms or genes, partakes ofthe double-edged gift of the trickster, providing power to both hurtand heal. An inventor of technology is often inspired by the discoveries ofscientists. Science as we know it today is younger than technology,dating back about 500 years to a period called the Renaissance.During the Renaissance, artists and thinkers began to explorenature systematically, and the first modern scientists, such asLeonardo da Vinci (1452–1519) and Galileo Galilei (1564–1642), ix

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x Modern Geneticsused instruments and experiments to develop and test ideas abouthow objects in the universe behaved. A succession of revolutionsfollowed, often introduced by individual geniuses: Isaac Newton(1643–1727) in mechanics and mathematics, Charles Darwin(1809–82) in biological evolution, Albert Einstein (1879–1955)in relativity and quantum physics, James Watson (1928– ) andFrancis Crick (1916–2004) in modern genetics. Today’s emerg-ing fields of science and technology, such as genetic engineering,nanotechnology, and artificial intelligence, have their own inspir-ing leaders. The fact that particular names such as Newton, Darwin, andEinstein can be so easily associated with these revolutions suggeststhe importance of the individual in modern science and technology.Each book in this set thus focuses on the lives and achievements ofeight to 10 individuals who together have revolutionized an aspectof science or technology. Each book presents a different field:marine science, genetics, astronomy and space science, forensic sci-ence, communications technology, robotics, artificial intelligence,and mathematical simulation. Although early pioneers are includedwhere appropriate, the emphasis is generally on researchers whoworked in the 20th century or are still working today. The biographies in each volume are placed in an order that reflectsthe flow of the individuals’ major achievements, but these life sto-ries are often intertwined. The achievements of particular men andwomen cannot be understood without some knowledge of the timesthey lived in, the people they worked with, and developments thatpreceded their research. Newton famously remarked, “If I have seenfurther [than others], it is by standing on the shoulders of giants.”Each scientist or inventor builds upon—or wrestles with—the workthat has come before. Individual scientists and inventors also inter-act with others in their own laboratories and elsewhere, sometimeseven partaking in vast collective efforts, such as the government andprivate projects that raced at the end of the 20th century to com-plete the description of the human genome. Scientists and inventorsaffect, and are affected by, economic, political, and social forcesas well. The relationship between scientific and technical creativityand developments in social institutions is another important facetof this series.

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PREFACE xi A number of additional features provide further context for thebiographies in these books. Each chapter includes a chronology andsuggestions for further reading. In addition, a glossary and a generalbibliography (including organizations and Web resources) appearat the end of each book. Several types of sidebars are also used inthe text to explore particular aspects of the profiled scientists’ andinventors’ work:Connections Describes the relationship between the featured work and other scientific or technical developments.I Was There Presents firsthand accounts of discoveries or inventions.Issues Discusses scientific or ethical issues raised by the discovery or invention.Other Scientists (or Inventors) Describes other individuals who played an important part in the work being discussed.Parallels Shows parallel or related discoveries.Social Impact Suggests how the discovery or invention affects or might affect society and daily life.Solving Problems Explains how a scientist or inventor dealt with a particular technical problem or challenge.Trends Presents data or statistics showing how developments in a field changed over time. Our hope is that readers will be intrigued and inspired by thesestories of the human quest for understanding, exploration, andinnovation. We have tried to provide the context and tools to enablereaders to forge their own connections and to further pursue theirfields of interest.

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eACKNOWLEDGMENTST hanks to the scientists in this book who reviewed their chapters and answered questions, and to the many assistants of sci-entists who patiently conveyed messages and sent (and some-times re-sent) photographs, permission forms, and other items.My thanks to my editor, Frank K. Darmstadt, as well for his helpand good humor; to my cats, for providing purrs and not knockingthe computer off my lap (though they tried); and, above all, to myhusband, Harry Henderson, for unending support, love, and every-thing else that makes life good. xiii

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e INTRODUCTION “Any sufficiently advanced technology is indistinguishable from magic.” —science fiction writer Arthur C. ClarkeM ost people love to watch magicians. These clever stage artists seem to make scarves or birds appear and then vanish again,“saw people in half” without really harming them, or escape fromboxes covered with chains and padlocks. A magic show almostguarantees an entertaining evening. Nonetheless, people have always had mixed feelings about magi-cians. Throughout history, they regarded men and women whocalled themselves magicians with both awe and suspicion. Was the“magic” merely a matter of illusions and tricks, or did it stem fromsome real, supernatural power? Would magicians make wishesand dreams come true, or would they cast evil spells that broughtdestruction? Concern about magicians’ powers and motives wasmade greater by the fact that magicians almost never explained howthey achieved their effects. Even when someone attempted an expla-nation, it was hard for most people to understand. Many people today have the same mixed feelings about scientistsand the technologists who build inventions upon science. They findscientists just as mysterious as magicians, and scientists’ “tricks”seem just as hard to comprehend. Because of this, some people maylet hopes and fears substitute for knowledge. Some believe thatscientists and inventors will end hunger, provide clean and inexpen-sive energy, and solve a host of other problems. Others feel equallysure that those same scientists and inventors will produce massiveenvironmental destruction or unstoppable epidemics. In both theirhopes and their fears, much of today’s public sees scientists and xv

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xvi Modern Geneticstechnologists as “playing God,” just as magicians were once accusedof doing. No field of knowledge except nuclear physics, whose discoveriesmade possible the atomic bomb, has been as much of a lightningrod for people’s hopes and fears about science as genetics and itstechnological offshoot, often called genetic engineering or biotech-nology. Even more than most scientists, geneticists and geneticengineers—people who analyze and sometimes change the inheritedinformation that controls the form and development of every livingthing—seem to wield magic power.Genetic Engineering Old and NewMany people think that genetics and genetic engineering are recentcreations, and in a strict sense this is true. The scientific field ofgenetics is only a little more than 100 years old. Researchers haveknown what genes are, physically and chemically, for a mere 50years, and they have been able to change genes directly for just halfthat time. In other ways, however, the study of genetics, and even geneticengineering, is as old as humankind. People have always noticedthat members of families tend to look alike, having similar hairor eye color, for instance. Sometimes parents and children share acertain trait or way of behaving, such as singing talent or a quicktemper. Those qualities seem to have been passed down from onegeneration to the next. People who observed such similarities wereseeing genetics in action. Similarly, ancient farmers and herders realized that if they mated,or bred, plants or animals with desirable traits such as the abilityto grow quickly or resist disease, they had a better than averagechance of obtaining offspring with those same traits. People werealso aware of characteristics such as strength and good health whenthey chose their own mates. In making decisions about mating andbreeding, individuals were acting as unconscious genetic engineers. Scientists began investigating inheritance of traits more system-atically in the mid-19th century. In On the Origin of Species, pub-lished in 1859, British biologist Charles Darwin claimed that nature,

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INTRODUCTION xviiin essence, behaved like plant and animal breeders. Characteristicsof living things changed randomly over time, he wrote, but only thefeatures that helped their possessors survive and reproduce contin-ued to appear in generation after generation. Darwin’s theory, whichhe called evolution by natural selection, caused great debate in hisown time, but almost all scientists now accept it. Only a few years later, Gregor Mendel (1822–84), an Austrianmonk, offered the first precise explanation of how the traits Darwinwrote about might be transmitted. By breeding pea plants in hismonastery garden, Mendel worked out rules that governed whichform of traits such as height and seed color would be passed fromparents to offspring. Mendel’s work, described in a paper published in 1866, was littleknown in his own time, but three European scientists independentlyrediscovered it at the start of the 20th century. Publicizing and build-ing on Mendel’s discoveries, these and other researchers of the timefounded the branch of science that British biologist William Bateson(1861–1926) named genetics, which studies the way traits are inher-ited. Early geneticists chose the term gene for a unit of inheritancethat conveys one trait, but no one knew what a gene actually was. Thomas Hunt Morgan (1866–1945) and his coworkers at ColumbiaUniversity performed breeding experiments on fruit flies in 1910that proved that inherited information was carried on chromosomes.Pairs (23 pairs in humans) of these minute “colored bodies” existin the nucleus, or central part, of cells. Chromosomes reproducethemselves just before a cell splits in two, so each new cell receives afull set. Morgan’s group showed that a genetic change, or mutation,that produced an unusual eye color in the flies had to be carried onthe same chromosome that determined a fly’s gender, because theeye color mutation occurred only in males. Males had been shownto possess a chromosome called the Y chromosome, which femalesdo not have. Morgan’s work told scientists where to look for genes. However,researchers still had no idea what substance in chromosomes con-tained genes or what chemical processes made genes able to repro-duce and transmit information. They knew they could never reallyunderstand how genes worked until they learned these secrets. Thesearch for the chemical nature of genes begins this book.

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xviii Modern GeneticsFifty Years of RevolutionThis volume in the Milestones in Discovery and Invention settells the stories of 14 of the most famous geneticists and geneticengineers who worked during the 50 years between the discoveryof the structure of DNA (deoxyribonucleic acid, the chemical thatproved to carry the “code” for an organism’s inherited traits) in1953 and the final reading out of the human genome, humanity’scomplete collection of genes, in 2003. James Watson and FrancisCrick in effect began the modern era of genetics by workingout DNA’s structure, which showed how DNA molecules couldreproduce and encode inherited information. Building on thisdiscovery, Crick and others in the 1960s deciphered the individualchemical “letters” that make up the DNA code and showed howthe code is used to make proteins, the substances that carry outmost activities in cells. In 1973, Herbert Boyer and Stanley N. Cohen showed that scien-tists could change genes, not only indirectly through breeding butdirectly through biochemical manipulations. Boyer and Cohen alsomoved genetic material from one organism to another and showedthat the material produced its normal proteins in its new location.In doing so, they invented what came to be called genetic engineer-ing. Boyer also pioneered the use of genetic engineering in industry,cofounding Genentech, the first biotechnology company. Unlike Watson and Crick’s discovery, genetic engineering quicklyattracted the attention of nonscientists as well as scientists. Writerssuch as Jeremy Rifkin, the president of the Foundation on EconomicTrends, warned that this new technology might create microbes thatwould cause unstoppable epidemics or other dangerous life-forms.Many later genetic engineering projects also drew criticism fromethicists, religious leaders, politicians, and others. A few years after Boyer and Cohen’s achievement, Michael Bishopand Harold Varmus revealed the genetic underpinnings of cancer,one of humanity’s most feared diseases. Genes able to produce can-cer in animals had been found in viruses, but Bishop and Varmusshowed in 1976 that the genes did not originate in these infectiousmicroorganisms. Instead, cancer-causing genes were normal cellu-lar genes gone awry. Other researchers later found several kinds of

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INTRODUCTION xixcancer-related genes in human tumors, opening up the possibility ofdeveloping drugs that would counteract the genes’ activity. French Anderson explored a more direct approach to controllinggenetic problems: repairing or replacing the defective genes them-selves. In 1991, Anderson and his coworkers inserted normal genesfor producing a key immune system chemical into blood cells of achild who suffered a rare inherited illness caused by lack of thischemical. This treatment, the first gene therapy given to a human,restored the young girl to health. Meanwhile, Nancy Wexler andothers tried to identify the mutated genes that produced inheriteddiseases such as Huntington’s disease, a brain-destroying ailmentthat afflicted Wexler’s family. Cooperative effort among severalresearch groups led to identification of the Huntington’s gene in1993. In that same year, Cynthia Kenyon identified genes in wormsthat lengthened the worms’ lifespan, hinting that genetic changesunderlay not only inherited illnesses but the much more commondiseases associated with aging. Few people opposed changing genes to prevent or treat inheritedillness, but some worried that the kind of gene alteration pioneeredby French Anderson might eventually be used to eliminate normalhuman variation or create “designer babies” that would be more likepurchased products than natural children. The work of Ian Wilmut,who announced in 1997 that he had cloned a sheep from a matureadult cell, and of James Thomson, who reported in 1998 that hehad isolated cells from human embryos (unborn living things in avery early stage of development) that might be used to create anytissue in the body, aroused similar concern about the implicationsthat these scientific advances might have for humanity. For manycommentators, both men’s research raised the frightening possibilitythat human beings might be cloned, even though neither scientistsupported such an activity. German-Swiss scientist Ingo Potrykus, whose laboratory usedgenetic engineering in 1998 to create rice containing a nutrient thatmany children in the developing world lack, encountered a differ-ent type of controversy. Potrykus said he wanted the rice to be aweapon against malnutrition, but critics claimed that agriculturalbiotechnology companies planned to use the rice as a tool to forcegenetically modified foods on an unwilling world.

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xx Modern Genetics Perhaps the loudest debates of all have arisen about the impli-cations of the Human Genome Project, a massive undertaking todetermine the complete genetic makeup of human beings. Duringthe project’s final years, media attention focused on the rivalrybetween Francis Collins, who led the international, government-sponsored project, and scientist-entrepreneur Craig Venter, whoheaded a private company that claimed it could complete thegenome analysis sooner and more inexpensively than the govern-ment effort could. Once the project was complete, however, discus-sion centered on the ways the genome information might be used.Observers say that understanding the human genome could lead togreatly improved treatments for disease, unprecedented discrimina-tion based on genetic makeup—or perhaps both.Moving Away from MagicMost scientists and inventors in the fields of genetics and geneticengineering welcome honest debate. They have usually thought hardabout where their work might lead, and they expect others to dothe same. Scientists and their supporters say, however, that beforeintelligent discussion can take place, people need to move beyondpicturing these men and women as magicians, possessors of secretknowledge and godlike powers. Nonscientists must learn how the“gene magicians” perform their tricks and what their technologycan and cannot accomplish. Only after gaining this knowledge,entering into the seeming magic themselves, will citizens be able tomake thoughtful decisions about how the amazing power to under-stand and alter the basic blueprints of life should be used. I hopethat this book will contribute to such education.

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1THE CODE OF LIFEFRANCIS CRICK, JAMES WATSON, AND THESTRUCTURE OF DNAR unning a race—especially an Olympic-level race, in which the winner may become world famous—is anything but easy. Thetask would become immeasurably harder if the contestants had torun the race blindfolded. The scientists in the race to discover thestructure of deoxyribonucleic acid (DNA) faced something like thatchallenge. Only a few “runners” entered the competition. At the start of the1950s, when the contest began, most potential entrants thought itwas not worth their trouble. Researchers had known for decadesthat chromosomes, the tiny bodies in the cell nucleus that had beenshown to carry inherited information (genes), were made of twokinds of complex chemicals: proteins and nucleic acids. One or theother of these groups of substances had to contain the information,coded somehow into the structure of their molecules. Most scien-tists who studied the subject thought that proteins would prove tobe the gene carriers. Proteins, after all, are made up of 20 kinds ofsmaller molecules called amino acids, which allowed for numerouscombinations within a protein molecule. Much less was knownabout nucleic acids, which Johann Miescher, a Swiss chemist, haddiscovered in 1869. However, biochemists had found that nucleicacids contain only four types of subunits, or bases. A chemical“alphabet” with four letters offered far fewer possibilities than onewith 20. Most researchers therefore believed that finding out theexact structure of nucleic acid molecules was not important. 1

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2 Modern GeneticsThe easy comradeship of Francis Crick (left) and James Watson (right) helpedthem work out the structure of DNA at Britain’s Cambridge University in1953. (Image 6.1, James D. Watson Collection, Cold Spring Harbor LaboratoryArchives)A Mystery MoleculeA small number of molecular biologists, members of a relativelynew scientific discipline that studies the structure and activitiesof molecules in living things, thought the protein supporterswere wrong. They pointed to an experiment done in 1944 inwhich Oswald Avery, a researcher at New York’s RockefellerInstitute, had mixed DNA from disease-causing bacteria witha living strain of related but harmless bacteria. After beingexposed to the DNA, the harmless bacteria—and their descen-dants—became able to cause disease. This change strongly sug-gested that DNA, a nucleic acid, carried inheritable informationthat the harmless bacteria had somehow incorporated into theirown genetic material.

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THE CODE OF LIFE 3 The molecular biologists who had been convinced by Avery’sexperiment realized that in order to learn how DNA might repro-duce itself and transmit inherited information, they needed to dis-cover the structure of the DNA molecule. They would have to work“blindfolded,” in the sense that earlier studies had provided very fewclues to guide them. The researchers knew that each DNA molecule contained manycopies of the four types of bases, small molecules called adenine,cytosine, guanine, and thymine. The molecule also included at leastone “backbone,” a long string of identical, alternating sugar and phos-phate molecules. X-ray crystallography, a technique that helped chem-ists analyze the shape of molecules, suggested that the backbone wasshaped like a coil, or helix. Austrian-born biochemist Erwin Chargaffhad shown in the late 1940s that the amount of cytosine in a DNAmolecule was always the same as the amount of guanine, and thesame was true of adenine and thymine. However, no one knew howmany backbone strands each molecule of DNA contained or how thebackbones and bases were arranged within the molecule.The Race BeginsIn 1951, three teams of molecular biologists, one in the United Statesand two in Britain, accepted their blindfolds and began the race tofind the structure of DNA. Chemist Linus Pauling, at the CaliforniaInstitute of Technology (Caltech), led the U.S. group. Pauling hadalready become famous for working out the basic structure of pro-tein molecules, which had also proved to be a helix. One of the British groups was at King’s College in London.Maurice Wilkins, a biophysicist from New Zealand, was its leader.British chemist Rosalind Franklin, an expert in X-ray crystallogra-phy, was among those who worked with him. Wilkins and Franklin,both brilliant scientists, did not get along with each other. Just the opposite was true of the third team, a pair of researchersat Cambridge, one of Britain’s two most famous universities. One ofthe duo was American, the other British. The United States scientist,James Dewey Watson, was the younger of the two. Born in Chicagoon April 6, 1928, Watson entered the University of Chicago as part

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4 Modern Geneticsof a special program when he was only 15 years old. At first heplanned to study birds, but by the time he obtained his B.S. in zool-ogy in 1947, physicist Erwin Schrödinger’s book What Is Life? haddrawn his interest to genetics and the possibility that certain mol-ecules might carry genetic information. Watson did graduate workon the genetics of viruses at Indiana University in Bloomington,receiving his Ph.D. in 1950. While doing further study in Europe, Watson met MauriceWilkins in spring 1951. Watson was already “obsessed,” as he laterput it, with DNA, and he believed that the DNA molecule’s structurewould hold the key to the way genes convey inherited information.When Wilkins told him that DNA could be studied by X-ray crys-tallography, Watson realized that this meant that DNA had regular,or repeated, features in its structure. Current Biography Yearbook1990 quotes Watson as saying he became convinced that the shapeof a DNA molecule would be “simple as well as pretty.” In fall 1951, Watson, then 23 years old, joined the CavendishLaboratory at Cambridge, where scientists were using X-ray crys-tallography to study protein molecules. There he met 35-year-oldBritish scientist Francis Harry Compton Crick. Born on June 8,1916, in Northampton, England, to a shoe manufacturer and hiswife, Crick still did not have his Ph.D. at the time he met Watson.The British scientist had received a B.S. in physics from UniversityCollege, London, in 1937, but World War II had interrupted hisscientific career. When he began his schooling once more, he foundhis interests turning toward biology. “I . . . immediately discovered the fun of talking to Francis Crick,”Watson’s Current Biography profile quotes him as saying. Crick, forhis part, wrote in his autobiography, What Mad Pursuit: Jim and I hit it off immediately, partly because our interests were astonishingly similar and partly, I suspect, because a certain youthful arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to both of us. The most important interest the two men shared was in DNA.They were sure that discovering its structure would make them

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THE CODE OF LIFE 5famous—if they could find the keyto the puzzle before the King’sCollege or the Caltech team did. Watson and Crick tried to solvetheir scientific problem mostly bythinking and talking. They alsobuilt models that showed possiblemolecular structures, just as LinusPauling had done when workingout the structure of proteins. Themodels let them see and manipulatepossible structures for the DNAmolecule in three dimensions.The Winning Discovery“In the process of [scientific] dis- New Zealand–born biophysicistcovery,” N. A. Tiley’s book on key Maurice Wilkins led the labora- tory at King’s College, London,DNA research, Discovering DNA, that competed with Watson andquotes eminent modern science Crick in the race to discoverhistorian Horace Freeland Judson the structure of DNA. (Nationalas saying, “there comes a unique Library of Medicine, photo B09719)moment: where great confusionreigned, the shape of an answersprings out—or at least the form ofa question.” Great confusion certainly reigned in the DNA race atthe start of 1953. Watson and Crick had made a preliminary guessabout DNA’s structure in late 1952, but Rosalind Franklin hadshown that they were wrong. Franklin, in turn, insisted that the mol-ecule could not have the overall shape of a helix, which also provedto be a mistake. Finally, Linus Pauling announced in January 1953that the DNA molecule contained three helix-shaped backbones.That conclusion was quickly shown to be incorrect as well. For James Watson, the shape of the answer to the DNA puzzlebegan to appear on January 30, 1953, when he visited MauriceWilkins at King’s College. Even though the two men were rivals inthe DNA race, they had become friends. During this visit, Wilkins

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6 Modern Geneticsshowed Watson an X-ray photograph that Rosalind Franklin hadmade of DNA. As Watson looked at this picture, which was clearerthan any others he had seen, “my mouth fell open and my pulsebegan to race,” he wrote later in his memoir of the DNA discovery,The Double Helix. He realized that the DNA molecule most likelyhad two parallel, helix-shaped backbones. Watson hurried back to Cambridge and described the photo toCrick. With the question of the backbones answered to their satis-faction, the pair turned their attention to the second major question:how the bases were arranged within the molecule. Crick concluded SOLVING PROBLEMS: X-RAY CRYSTALLOGRAPHY British physicist Lawrence Bragg invented X-ray crystallography in 1912. In this technique, a beam of X-rays is passed through a solid. Some of the rays bounce off atoms in the molecules within the solid, thereby changing the angles at which the rays strike a photographic plate on the other side of the solid. A photograph made from the plate shows a pattern of dark dots or smears on a light background. Interpreted by experts, photos of this kind reveal information about the three-dimensional placement of atoms within molecules—in other words, the molecules’ structure. At first, Bragg and his followers applied X-ray crystallography only to solids that had an orderly structure, which let the solids form crystals. In 1934, however, Desmond Bernal and W. T. Astbury, two other British scientists, showed how to use the technique to analyze substances with large, complex molecules that cannot form crystals, such as proteins and nucleic acids. Rosalind Franklin was a specialist in this new type of X-ray crystallography. Franklin and other experts such as Dorothy Crowfoot Hodgkin used X-ray crystallography to work out the structure of many impor- tant biological molecules, including cholesterol and penicillin, during the late 1930s and 1940s. They became able to unravel even more complex substances in the 1950s, when computers took over the difficult mathematical calculations involved in interpreting the X-ray photographs.

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THE CODE OF LIFE 7that the bases must be inside the backbones, stretching betweenthem like steps on a twisted ladder. At first, Watson thought thebases might appear as pairs of the same kind of molecule—adenineand adenine, for example. That did not fit what was known aboutthe size of the space between the backbones, however. Too impatient to wait for new metal models to be built, Watsoncut model pieces from cardboard and began trying different arrange-ments. Two of the bases, adenine and guanine, were larger than theother two. Pairs of large bases were too big to fit between the inter-twined backbones, and pairs of the smaller bases were too small.As Watson played with his cardboard cutouts, however, he noticedthat a pair consisting of adenine, a large base, and thymine, a smallone, had exactly the same size and shape as a pair made up of gua-nine and cytosine. Both types of pair fit nicely if placed horizontallybetween the two vertical backbones, just as Crick had suggested. Apairing of adenine with thymine and guanine with cytosine wouldalso fit with Erwin Chargaff’s finding about the proportions ofbases in the DNA molecule. Bonds between the bases’ hydrogenatoms could hold the pairs together, Watson believed. As soon as Crick came into their shared office on the morningof February 28, Watson showed him the matching cardboard basepairs. Crick saw immediately that Watson’s discovery meant that thesequence, or order, of the bases along the two backbones was com-plementary. If a person knew the sequence of bases attached to onebackbone, the order of bases along the other could be predicted. Watson and Crick wrote a short scientific paper that describedtheir proposed structure. The paper appeared in the prestigiousBritish science journal Nature on April 25, 1953. Only one under-stated sentence near the end of the report hinted at the discovery’simportance: “It has not escaped our notice that the specific pairingwe have postulated immediately suggests a possible copying mecha-nism for the genetic material.”How DNA ReproducesOn May 30, 1953, about five weeks after Watson and Crick’sinitial paper appeared, the two scientists published a second paper

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8 Modern Geneticsin Nature that explained the cryptic sentence in the first. If DNAcarried hereditary information, Crick and Watson said, DNA mol-ecules had to be able to reproduce themselves when chromosomesduplicated during cell division. The two men believed that the keyto DNA’s reproduction lay in the molecule’s mirror-image struc-ture. Just before a cell divides, they proposed, the weak hydrogenbonds between the pairs of bases in its DNA molecules break. Eachmolecule then splits lengthwise, like a zipper unzipping. Each baseattracts its pair mate, complete with an attached backbone segment,from among free-floating materials in the cell nucleus. An adeninemolecule always attracts a thymine and vice versa, and the same for I WAS THERE: THE SECRET OF LIFE In The Double Helix, James Watson described the moment when he told Francis Crick about his proposed structure for the DNA molecule on February 28, 1953: Upon his arrival Francis did not get more than halfway through the door before I let loose that the answer to everything was in our hands. Though as a matter of principle he maintained skepticism for a few moments, the similarly shaped A-T and G-C pairs had their expected impact. Crick began experimenting with Watson’s cardboard models himself and made several refinements to Watson’s structure. Both men were soon convinced that they had essentially solved the DNA problem, although Watson remained cautious. We both knew that we would not be home [completely sure their structure was right] until a complete model was built in which all the [features fitted with the X-ray data]. There was also the obvious fact that the implications of its existence were far too important to risk crying wolf. Thus I felt slightly queasy when at lunch Francis winged into the Eagle [a nearby bar] to tell everyone within hearing distance that we had found the secret of life.

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THE CODE OF LIFE 9James Watson and Francis Crick deduced in 1953 that each molecule of deoxy-ribonucleic acid (DNA) is made up of two “backbones” composed of alternat-ing smaller molecules of phosphate (P) and deoxyribose (D), a sugar. The back-bones both have the shape of a helix, or coil, and they twine around each other.Inside the backbones, like rungs on a ladder, are four kinds of smaller moleculescalled bases. The bases always exist in pairs, connected by hydrogen bonds.Adenine (A) always pairs with thymine (T), and cytosine (C) always pairs withguanine (G).

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10 Modern Geneticscytosine and guanine. When the process is complete, the nucleuscontains two identical double-stranded DNA molecules for everyone that had existed before. The cell now splits, and each of the twodaughter cells receives a complete copy of the original cell’s DNA.Experiments later confirmed this theory. Watson and Crick’s discovery of DNA’s structure earned themthe Nobel Prize in physiology or medicine in 1962. Maurice Wilkinsalso shared in the prize. Rosalind Franklin could not, becauseshe had died in 1958, and Nobel prizes are never awarded aftera person’s death. Numerous other awards, most given to Watsonand Crick jointly, honored the same groundbreaking achievement,including the Albert Lasker Award for Basic Medical Research(1960), the Prix Charles Leopold Meyer from the French Academyof Sciences (1961), and the Research Corporation Award (1962).Watson also won the Medal of Freedom (1977) and the NationalMedal of Science (1997).The Genetic CodeAfter his and James Watson’s breakthrough discovery, Francis Crickcontinued to do research on DNA at Cambridge. (He received hisPh.D. from that institution in 1953.) He wanted to learn how aDNA molecule carries information and how it uses that informa-tion to make proteins, which other scientists had shown to be genes’chief task in the cell. The actions of proteins, in turn, create thetraits that show themselves in living things. Crick and Sydney Brenner, a fellow Cambridge scientist, proposedin 1955 that the sequence of bases in a DNA molecule acts as a codeto determine the sequence of amino acids in protein molecules. Each“letter” of the code, the two researchers suggested, is a set of threebases arranged in a particular order. With four bases to work with,there could be 64 (4 × 4 × 4) such combinations, more than enoughto represent all 20 amino acids. Marshall Nirenberg of the National Institutes of Health andother molecular biologists set out to “crack” the DNA code in theearly 1960s, determining by experiment which amino acid eachset of three bases stood for. They learned that several different

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THE CODE OF LIFE 11DNA’s structure explains its power to duplicate itself. When a cell prepares todivide, the hydrogen bonds between the bases dissolve and the DNA moleculesplits along its length like a zipper unzipping. Each half then attracts bases andbackbone pieces from among the molecules in the cell, forming the same pairs ofbases that had existed before. The result is two identical DNA molecules.

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12 Modern Genetics OTHER SCIENTISTS: ROSALIND FRANKLIN (1920–1958) Rosalind Elsie Franklin was born on July 25, 1920, in London. Her well-to-do father at first discouraged her interest in science because he believed that higher education and careers made women un- happy. She persisted, however, and eventually studied chemistry at Newnham, a women’s college in Cambridge University, graduating in 1941. Franklin did research on the structure of carbon molecules for the Coal Utilization Research Association during World War II and earned a Ph.D. from Cambridge on the basis of this work in 1945. Franklin learned X-ray crystallography while doing research in France after the war. She became especially skilled at using the tech- nique to study compounds that did not form crystals, which included most biological chemicals. This expertise brought her to Maurice Wilkins’s laboratory at King’s College, part of the University of London, in 1950. Wilkins hoped Franklin could take photographs that would help the group determine the structure of DNA molecules. Some of Franklin’s photographs were brilliant, and one of them helped James Watson and Francis Crick solve the puzzle of DNA’s structure. (Wilkins has been criticized for showing this photograph to Watson without asking Franklin’s permission first, but he felt that, as head of the laboratory, he had the right to do so.) Watson and others have said that Franklin herself might have worked out the DNA structure if she had had a scientific partner with whom she felt comfortable sharing her ideas. Franklin left Wilkins’s laboratory around the time Watson and Crick published their first DNA paper. She spent the rest of her all-too-short career studying the structure of viruses at Birkbeck, another college in the University of London. Franklin died of ovarian cancer in 1958, when she was only 38 years old, leaving forever unsettled the question of whether she would have shared in the 1962 Nobel Prize given to Watson, Crick, and Wilkins. According to Franklin biographer Anne Sayre, J. D. Bernal, the X-ray crystallography expert under whom Franklin worked at Birkbeck, said of her, “As a scientist Miss Franklin was distinguished by extreme clarity and perfection in everything she undertook. Her photographs are among the most beautiful X-ray photographs . . . ever taken.”

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THE CODE OF LIFE 13As a first step in making a protein, part of a DNA molecule (a gene) uses itselfas a pattern to form a matching stretch of messenger RNA (mRNA). When themessenger RNA moves into the cytoplasm of the cell, it attracts matching shortstretches of transfer RNA (tRNA), each of which tows a single amino acid mol-ecule. With the help of an organelle called a ribosome, the transfer RNA mol-ecules lock onto the matching parts of the messenger RNA, and the amino acidsthey carry are joined, forming a protein.

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14 Modern Geneticsbase triplets often stood for the same amino acid. Some additionalgroups marked the beginning or end of a gene. (Each DNA moleculecontains hundreds or even thousands of genes.) By 1965, researchershad a “dictionary” that included all 64 three-base combinations. While the details of the code were being worked out, Crick,Brenner, and others were learning the mechanism by which DNAuses its code to make proteins. Crick and Brenner suggested thatDNA makes a copy of itself in the form of RNA (ribonucleic acid),which is like DNA except that it has a different kind of sugar in itsbackbones, and in place of thymine it has a different base, uracil.DNA normally cannot leave a cell’s nucleus, but its RNA copy, whichcame to be called messenger RNA, can travel into the cytoplasm,the jellylike material that makes up the outer part of the cell. In the cytoplasm, Crick and Brenner said, the messenger RNAencounters small bodies called ribosomes. A ribosome rolls alongthe messenger RNA molecule and attracts from the cytoplasm theamino acid represented by each three-base “letter” of the translatedDNA code. Crick believed that what he called adapter molecules(later called transfer RNA) tow the amino acids to the correct spotson the messenger RNA. The amino acids then join together, form-ing the protein. The messenger RNA and the ribosome release theprotein molecule into the cell. Brenner and other researchers in theearly 1960s proved that this theory was essentially correct.Diverging CareersFrancis Crick remained a researcher all his life. From the mid-1960sto the mid-1970s he studied the way animals develop before birth.In 1977, he moved to the Salk Institute for Biological Studies in LaJolla, California, and began to focus on the brain. Working mostlyat a theoretical level, he investigated the way mammals’ brainsinterpret visual data and process information during dreaming. Healso wrote books on various subjects, including the possible originof life and the nature of consciousness. Crick died of cancer on July28, 2004. James Watson, by contrast, eventually exchanged laboratorywork for teaching and administration. He returned to the United

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THE CODE OF LIFE 15States soon after his famous discovery. He spent most of the next15 years researching the structure of RNA and, like Crick (althoughindependently of his former partner), the part that this nucleic acidplayed in the making of proteins. Beginning in 1956, Watson alsotaught at Harvard University. Watson became director of Cold Spring Harbor Laboratory (CSHL)on Long Island, New York, in 1968. He left Harvard in 1976 to workat CSHL full time. He modernized this famous laboratory, the firstgenetics laboratory established in the United States, and focused itsresearch on the biology of cancer, which was proving to be intimatelyrelated to genetics. Watson was president of CSHL from 1994 to2003, after which he became the institution’s chancellor. Watson also found that he had literary skills. His memoir of theDNA race, The Double Helix, became a best seller when it waspublished in 1968. Some critics complained about his harsh portraitsof other scientists, especially Rosalind Franklin, but readers enjoyedhis breezy writing style and the book’s behind-the-scenes picture ofscientists at work. According to a 2004 Chicago Tribune article byWilliam Mullen, Watson says he is more proud of this book than ofhis codiscovery of DNA’s structure. “The DNA structure was goingto be found within two or three years, anyway,” Watson claimed.“But my book was my creation, something nobody else could havedone.” Watson later wrote many other books, including a secondvolume of autobiography and a highly regarded textbook on themolecular biology of genes. In 1989, when Watson was 60 years old, the U.S. government chosehim to direct the newest and biggest genetic project of all: the inter-national Human Genome Project, sometimes called “biology’s moonshot.” Watson resigned this position in 1992, but he remains a strongsupporter of the genome project and of genetic research in general. The Companion to the History of Modern Science quotes HoraceFreeland Judson as saying that “biology has proceeded by ‘openingsup’” rather than through the complete changes of world view thatoften occurred in physics. James Watson and Francis Crick’s discov-ery of the structure of DNA sparked one of the biggest “openings up”of all. Nobel-winning scientist and science historian Peter Medawar,quoted in Dennis L. Breo’s article about Watson and Crick’s achieve-ment in the Journal of the American Medical Association (February

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16 Modern Genetics24, 1993), said that the unraveling of the structure of DNA and thelater discoveries built on it make up “the greatest achievement ofscience in the 20th century.”Chronology1869 Johann Miescher discovers nucleic acids1912 British physicist Lawrence Bragg invents X-ray crystallography1916 Francis Crick born on June 8 in Northampton, England1928 James Watson born on April 6 in Chicago, Illinois1944 Oswald Avery shows that bacteria’s inherited traits can be changed by exposing them to pure DNA1940s Late in the decade, Erwin Chargaff shows relationship among quantities of bases in DNA1950 Watson obtains Ph.D. from University of Indiana, Bloomington1951 Watson meets Maurice Wilkins in the spring and learns that the DNA molecule has repeating features in its structure Watson and Crick meet at Cambridge University in England in the fall1952 Watson and Crick make a tentative proposal about DNA’s structure late in the year; Rosalind Franklin proves them wrong Franklin insists that the DNA molecule cannot be a helix1953 Linus Pauling proposes an incorrect structure for DNA in January On January 30, Maurice Wilkins shows Watson an X-ray photograph of DNA made by Rosalind Franklin Watson and Crick work out the structure of the DNA molecule on February 28 On April 25, Nature publishes Watson and Crick’s paper describing their proposed structure of the DNA molecule

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THE CODE OF LIFE 17 On May 30, Nature publishes a second paper, in which Watson and Crick propose a mechanism by which a DNA molecule could make a copy of itself Late in the year, Crick receives his Ph.D. from Caius College, Cambridge1955 Crick and Sydney Brenner propose that the sequence of bases in DNA is the code by which the molecule orders the assembly of proteins and that each “letter” of the code consists of three bases in a certain order Crick and Brenner suggest a mechanism by which DNA arranges the making of proteins through use of an intermediate molecule, RNA1956 Watson joins faculty of Harvard University1958 Rosalind Franklin dies of ovarian cancer1961–1965 Marshall Nirenberg and others decipher the genetic code Sydney Brenner and others verify the process by which DNA makes proteins1962 Watson, Crick, and Maurice Wilkins win Nobel Prize for their discovery of structure of DNA1968 Watson becomes director of Cold Spring Harbor Laboratory Watson’s memoir of his DNA discovery, The Double Helix, is published and becomes a best seller1976 Watson leaves Harvard to work at Cold Spring Harbor Laboratory full time1977 Crick moves to Salk Institute for Biological Studies in La Jolla, California, and begins theoretical studies of the brain1989 Watson named ﬁrst director of Human Genome Project1992 Watson resigns as head of Human Genome Project1994 Watson becomes president of Cold Spring Harbor Laboratory2003 Watson steps down as president of Cold Spring Harbor Laboratory and becomes the institution’s chancellor2004 Francis Crick dies on July 28

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18 Modern GeneticsFurther ReadingBooksCrick, Francis. What Mad Pursuit. New York: Basic Books, 1988. Crick’s autobiography, including his recollections about the discovery of DNA’s structure.Edelson, Edward. Francis Crick and James Watson and the Building Blocks of Life. New York: Oxford University Press, 1998. Account of the famous discovery, written for high school students.Friedberg, Errol C. The Writing Life of James D. Watson. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 2004. Surveys Watsons books and essays.Judson, Horace Freeland. The Eighth Day of Creation. New York: Simon and Schuster, 1979. Describes Watson and Crick’s discovery of DNA’s structure and other key discoveries in genetics and molecular biology from the mid-1930s to about 1970.Olby, R. C., et al., eds. Companion to the History of Modern Science. London: Routledge, 1990. Essays describe different aspects of the history of science.Sayre, Anne. Rosalind Franklin and DNA. New York: W. W. Norton, 1975. Biography strongly sympathetic to Franklin provides a view of the DNA race that contrasts to Watson’s.Tiley, N. A. Discovering DNA. New York: Van Nostrand Reinhold, 1983. Describes Watson and Crick’s and other discoveries about DNA in the mid-20th century.Watson, James D. The Double Helix. New York: Atheneum, 1968. Lively but biased memoir about the discovery of the structure of DNA.ArticlesBreo, Dennis L. “The Double Helix—Watson and Crick’s ‘Freak Find’ of How Like Begets Like,” Journal of the American Medical Association 269 (February 24, 1993): 1,040–1,045. Recalls how Watson and Crick made their discovery 40 years previ- ously.

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THE CODE OF LIFE 19“Crick, Francis (Harry Compton).” Current Biography Yearbook 1983, 68–71. New York: H. W. Wilson, 1983. Profile of Crick summarizes other material written about him up to that time.Mullen, William. “Genetic Pioneer James Watson Recalls a Chicago Education.” Chicago Tribune, 4 February 2004, n.p. Describes Watson’s Chicago roots and later achievements.Watson, J. D., and F. H. C. Crick. “Genetical Implications of the Structure of Deoxyribonucleic Acid,” Nature, 30 May 1953, pp. 964–967.Scientific paper describing how DNA’s structure could allow it to reproduce itself.———. “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid,” Nature, 25 April 1953, pp. 737–738. The short scientific paper in which Watson and Crick propose a struc- ture for the DNA molecule.“Watson, James (Dewey).” Current Biography Yearbook 1990, 605–607. New York: H. W. Wilson, 1990. Biographical article about Watson includes quotes from several inter- views.Web SitesAccess Excellence. This site for health and bioscience teachers and learners, sponsored by the National Health Museum, includes bio- graphical profiles of Francis Crick and James Watson, interviews with them, and an account of their discovery of DNA’s structure. www.accessexcellence.org. Accessed on December 29, 2004.

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2 GENE SANDWICHES TO GO HERBERT BOYER, STANLEY N. COHEN, AND THE BIRTH OF GENETIC ENGINEERINGI t seems fitting that genetic engineering, in a sense, started in a delicatessen. Like the server behind the counter in a deli, geneticengineers can slice genes to order, sandwich them together withgenes from other living things, and wrap up the package “to go.” Indoing so, they create completely new kinds of organisms. Both sup-porters and critics of genetic engineering agree that this technologyopens up possibilities that will greatly affect science, human society,and perhaps all life on Earth.A Chat over Corned BeefThe deli where genetic engineering was born is in Honolulu, Hawaii.Molecular biologists Stanley Norman Cohen of Stanford Universityand Herbert Wayne Boyer of the University of California, SanFrancisco (UCSF), dropped into the eatery one evening in November1972, following a long day of meetings at a scientific conference. Cohen, born in Perth Amboy, New Jersey, on February 17, 1935,had heard a speech that Boyer gave that day, and he was eagerto learn more about the work the UCSF researcher was doing.When Cohen began to talk about his own research, Boyer became 20

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GENE SANDWICHES TO GO 21equally interested. As they devouredtheir pastrami and corned beef sand-wiches, the two men came to realizethat their areas of expertise fittedtogether as neatly as the pairs of basesin a DNA molecule. By joining forc-es, they thought they might be ableto do something truly remarkable. A husky former high school foot-ball star from Derry, Pennsylvania,Boyer was a year and a half youngerthan Cohen, having been born onJuly 10, 1936. Boyer had studiedbiology and chemistry at St. VincentCollege in Pennsylvania, obtaining abachelor’s degree in 1958. He earnedhis master’s degree in 1960 and hisPh.D. in 1963 from the University of During a conversation in a Hawaiian delicatessen,Pittsburgh. After doing postgradu- Stanley N. Cohen of Stanfordate work at Yale University, Boyer University helped plan thejoined the UCSF faculty in 1966 as experiments that led to genetican assistant professor. engineering. (Stanford University) As Boyer explained to Cohen inthe delicatessen, he was currentlyworking with restriction enzymes, chemicals that certain bacteriamake. These “molecular scissors” slice through strands of DNAwherever they find a particular sequence of bases. The bacteria usethe enzymes to cut invading viruses apart before the viruses can repro-duce and kill the bacteria. Boyer believed that the enzymes offered away to divide immensely long DNA molecules into manageable—andpredictable—chunks. Different restriction enzymes cut DNA at differ-ent sequences, so molecular biologists could choose how they wouldslice their DNA by deciding which enzyme to use. One of the most interesting things about restriction enzymes, Boyertold Cohen, was that these “scissors” were not very sharp. Insteadof cutting cleanly through a DNA molecule, they left an incompletesequence of bases dangling from each end of the cut piece. Just ashappened when DNA reproduced, these dangling bases were strongly

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22 Modern Geneticsattracted to other bases that would complete their usual pairings.That meant that the sequence from one snipped piece of DNA wouldattach easily to the opposite end of another piece of DNA that hadbeen cut by the same enzyme, even if the two DNA fragments camefrom different kinds of living things. Other enzymes called ligasescould then be used to glue the “sticky ends” together. Cohen, whose background included a bachelor’s degree fromRutgers University (1956) and an M.D. from the University ofPennsylvania School of Medicine (1960), had come to Stanford in1968. He told Boyer that his own work with bacteria involved someunusual features of the microorganisms’ genetics. In 1965, he said,scientists had discovered that, in addition to the large, ring-shapedDNA molecule that carries most of the bacteria’s genetic informa-tion, bacteria often contain smaller rings of DNA called plasmids.Each plasmid holds only a few genes. When a bacterium reproducesitself by splitting in half, it reproduces not only its main genome butany plasmids it contains as well. Bacteria do not exchange genes through sex, as many living thingsdo. However, they sometimes exchange plasmids during a processcalled conjugation. In 1971, Cohen had found a way to imitate con-jugation, removing plasmids from bacterial cells and making otherbacteria take up the DNA pieces. He hoped to use this technique tohelp other scientists analyze individual genes or segments of DNA.Such analysis required millions of identical copies of a gene. Bacteriamultiply at amazing speed, doubling their number every 20 minutes,so a single bacterium can produce millions more like itself in a singleday. Cohen hoped that if he could find a way to insert a gene into theDNA of plasmids and then put the plasmids into bacteria, the bacte-ria would copy, or clone, the added gene as they reproduced. Boyer’senzymes, Cohen now realized with mounting excitement, might offerjust the tools he needed to break open the rings of plasmid DNA, addthe genes he wanted to copy, and reseal the plasmids.The First Gene SplicingBy the time Boyer and Cohen had finished their sandwiches, the tworesearchers had planned a series of experiments that would combine

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GENE SANDWICHES TO GO 23Herbert Boyer told Stanley Cohen that restriction enzymes, made by bacteria,could cut DNA molecules at certain sequences, leaving short pieces of single-stranded DNA at both ends of each segment. Each single-stranded piece can“stick to” any other single-stranded DNA piece containing a complementarysequence of bases. Cohen and Boyer realized that this fact might allow them tocombine segments of DNA from different species.

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24 Modern Geneticstheir knowledge. In spring 1973, after they returned to California,they began carrying out those experiments. With the help ofcoworkers Annie Chang and Robert Helling, the two first used oneof Boyer’s restriction enzymes to cut open some of Cohen’s plas-mids. As Cohen had hoped, the “sticky ends” left by the inefficientmolecular scissors let them join two different plasmids together tomake a single large one. Cohen called the new plasmid a chimera,after a monster from ancient Greek legend that was part lion, partgoat, and part snake. The plasmids used in Cohen and Boyer’s first experiment came fromtwo different strains of Escherichia coli, a common and usually harm-less bacterium that lives in the human intestine. One plasmid carried agene that made the bacteria resistant to the antibiotic tetracycline, whilethe other had a gene that produced resistance to kanamycin, a differentantibiotic. Boyer and Cohen put the altered plasmids into bacteria thatnormally would be killed by both types of drug, and then transferredthe bacteria to a culture dish containing the two antibiotics. Some ofthe bacteria survived, showing that both of their newly acquired resis-tance genes were making proteins. For the first time, human beings hadmoved genes from one type of living thing to another and proved thatthe genes could function afterward. In a second experiment, Boyer and Cohen combined plasmidsfrom two different species of bacteria. A third test went still further,putting a gene from a frog into a plasmid. In both cases, the newplasmids functioned when put into bacteria, and they were copiedwhen the bacteria multiplied. The bacteria containing these plas-mids were essentially new kinds of organisms. Cohen called his and Boyer’s new technique “recombinant DNA.”It later became known colloquially as gene splicing. Although a2004 Genomics and Genetics Weekly article quotes Cohen as say-ing, “Herb and I didn’t set out to invent genetic engineering. We setout to study basic biological phenomena,” other molecular biolo-gists were quick to realize the potential value of the pair’s research.After hearing Boyer describe the work at a scientific meeting in1973, according to Edwin Shorter’s book on the development ofthe National Institutes of Health, The Health Century, one scientistsummed up everyone’s reaction by saying, “Well, now we can puttogether any DNA we want to.”

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RUNNING HEAD RIGHT 25 Figure #8 Full height: 29p5 Option allowing for 3 lines of text: 24p4In one of their groundbreaking gene-splicing experiments, Stanley Cohen andHerbert Boyer broke up cells of a common bacterium, E. coli, and took outsmall, ring-shaped pieces of DNA called plasmids. They then used a restrictionenzyme to cut the plasmids open. They used the same enzyme to produce seg-ments of DNA from the cells of frogs. The bacterial and frog DNA segmentsjoined together because of the complementary “sticky ends” of single-strandedDNA attached to each segment. Boyer and Cohen used a ligase, another type ofenzyme, to bind the segments together, creating a new plasmid that containedfrog as well as bacterial DNA. The researchers then inserted the plasmids car-rying the foreign genes into other E. coli bacteria and showed that the foreigngenes could make their normal proteins. When the bacteria multiplied, theadded genes were duplicated along with the bacteria’s own genetic material.

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26 Modern GeneticsIs Genetic Engineering Dangerous?Two floors above Cohen’s laboratory at Stanford was the labo-ratory of another molecular biologist, Paul Berg. Berg mighthave created genetically engineered organisms before Cohen andBoyer—if concern about the possible results of his experimentshad not stopped him. A few months before Boyer and Cohen’s experiments began, Bergremoved a gene from SV40, a type of virus that infects monkeys,and combined it with the genome of another virus called lambda,which attacks bacteria. Lacking Boyer’s restriction enzymes, hepainstakingly attached “sticky” pieces of single-stranded DNA tothe ends of his virus genes by chemical means. He then joined thegenetic pieces with a ligase. Berg thus became the first person tocombine genes from two different types of living things. He did notput the genes into an organism or prove that they could still func-tion, however. Berg had planned to use lambda as a vector, or carrier, to insertSV40 genes into E. coli. When Robert Pollack, a geneticist work-ing at Cold Spring Harbor Laboratory in Long Island, New York,heard about this proposed experiment, however, he phoned Berg inalarm. SV40 was harmless in monkeys, Pollack pointed out, but itcaused cancer in mice and hamsters. Pollack was worried about thepossible dangers of inserting genes from a cancer-causing virus intoa bacterium that could live inside the human body. Berg decided that it would be wise to heed Pollack’s warning, andhe called off his experiments. When he heard about the work beingdone by Boyer, Cohen, and others, he became concerned about thesafety of some of their projects as well.Setting StandardsLate in 1973, Berg and 77 other molecular biologists sent a letterto the prestigious American scientific journal Science. It asked theU.S. National Academy of Sciences to look into possible dangersof recombinant DNA research and establish safety guidelines forexperiments in this new field.

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GENE SANDWICHES TO GO 27OTHER SCIENTISTS: PAUL BERG (1926– )Born on June 30, 1926, in Brooklyn, New York, Paul Berg was the sonof a clothing manufacturer. His study of biochemistry at PennsylvaniaState College was interrupted by World War II, in which he foughtin the navy. He finally obtained his bachelor’s degree in 1948. Heearned a Ph.D. in biochemistry from Western Reserve University, nowCase Western Reserve, in Cleveland, Ohio, in 1952. Before he cameto Stanford in 1959, he taught at the Washington University Schoolof Medicine in St. Louis. Berg’s first major research achievement, made in 1956, provedpart of Francis Crick and Sydney Brenner’s theory about how pro-teins were made. Crick and Brenner had suggested a year earlier thatsmall molecules that they called adapter molecules towed individualamino acids into place and attached them to growing protein mol-ecules. Berg found the first type of adapter molecule (transfer RNA)to be identified and showed that it always attached itself to an aminoacid called methionine. The work Berg was doing in 1972 and 1973 also grew out of dis-coveries by Watson and Crick. After the two scientists worked outthe structure of DNA, they proposed that the double-stranded DNAmolecule would reproduce by splitting apart. Each of the resultingsingle strands would then rebuild its partner strand by attractingfree-floating bases in the cell. Berg demonstrated that short singlestrands of DNA did stick to other strands containing a complemen-tary sequence of bases. For instance, a strand with the sequenceC-A-A-T-G would bond to one with the sequence G-T-T-A-C. Berg’s planned experiment of combining virus genes and trying tomake the altered viruses put the combined genes into bacteria wasa first step toward introducing new genes into cells from mammals,James Watson (with Andrew Berry) writes in DNA: The Secret of Life,his history of DNA research. Eventually, Watson says, Berg hopedto use viruses to carry healthy genes into the cells of people withgenetic diseases. Almost two decades later, French Anderson andothers employed this same idea in developing gene therapy. Berg won a share of the Nobel Prize in chemistry in 1980 for hispioneering work on the biochemistry of genes. He has also receivedother awards, including the Albert Lasker Award for basic medicalresearch (1980) and the National Medal of Science (1985).

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28 Modern Genetics The scientists’ call for caution went still further in a secondletter, published in July 1974. Berg, Boyer, Cohen, and the othersigners of the letter asked other researchers in the field to agree toa moratorium, or temporary halt, for some kinds of gene-alteringresearch until the possible hazards of such work had been evaluatedand more adequate safety precautions had been developed. The sci-entists were afraid that bacteria with dangerous added traits, suchas the power to cause cancer or resist antibiotics, might escape fromgenetic engineers’ laboratories and infect humans. These safety fears resulted in a groundbreaking meeting of 140molecular biologists at Asilomar, a retreat center in central California, ISSUES: CONTINUING SAFETY CONCERNS Most experts now think that the chances of a dangerous genetically modified microorganism escaping a laboratory on its own are small. Especially after the al-Qaeda attacks of September 2001, however, fear has grown that terrorists might create and release such deadly microbes deliberately. Defectors from Soviet biological warfare labo- ratories reported in the 1990s that the laboratories had conducted genetic engineering experiments on disease-causing bacteria, for instance. Two experiments in the early 2000s were innocent in themselves, but they showed how easy creating a deadly microorganism could be. In the first experiment, described in February 2001, Australian scientists genetically altered the virus that causes mousepox, a dis- ease similar to the often fatal human disease smallpox, and thereby accidentally made a virus that could kill mice vaccinated against the standard form of mousepox. Secondly, scientists at the State University of New York at Stony Brook reported in July 2002 that they had used information available on the Internet and DNA pur- chased through the mail to create “from scratch” a virus capable of causing the crippling disease polio. Members of Congress and even some scientists questioned whether accounts of research of this kind should be published, saying that terrorists might read them and put the methods described in the reports to terrible use.

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GENE SANDWICHES TO GO 29in February 24–27, 1975. The meet-ing was also spurred by a secondconcern: the possibility that if scien-tists did not establish rules for thisnew technology, legislators would.Alarming stories about genetic engi-neering were beginning to appear innewspapers, radio, and television,and the public was demanding thatthe technology be controlled. By the end of their argumenta-tive meeting, the Asilomar grouphad devised guidelines for con-ducting different types of gene-splicing experiments. The NationalInstitutes of Health (NIH), thechief research institutions spon-sored by the U.S. government, used Herbert Boyer not only co- developed genetic engineering butthe Asilomar guidelines as a model helped found the modern biotech-when it drew up its own safety rules nology industry. (Albert and Maryin 1976. The NIH rules were bind- Lasker Foundation)ing on all scientists receiving fund-ing from the federal government,and most other U.S. researchers,especially those at universities, agreed to follow them as well. TheNIH also established the Recombinant DNA Advisory Committee(RAC) to review future genetic engineering experiments. These government steps quieted public fears. After several yearsof gene-splicing experiments passed without major problems, mostof the NIH rules were dropped in 1980. The RAC, however, remainsin existence. Its main job is to review experiments or drug tests inwhich altered genes are transferred into humans (gene therapy).Bacterial BonanzasEven while scientific and public fear of gene splicing was at its height,excitement about the new technology’s promise was equally strong.

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30 Modern GeneticsMany people hoped that genetic engineering would produce newways to treat disease or increase the world’s food supply. In addi-tion, farsighted businesspeople began to suspect that gene alterationmight help them make a great deal of money. Herbert Boyer was one of the first scientists to grasp this idea.Early in 1976, Robert Swanson, a 27-year-old venture capitalist,persuaded Boyer to join him in starting a business that would usegenetic engineering techniques. The two men called their companyGenentech, for GENetic ENgineering TECHnology. Genentech, like similar companies formed soon afterward byother scientists and entrepreneurs, drew on Boyer and Cohen’sdiscovery that foreign genes put into bacteria could produce theproteins that the genes had made in their original location, evenif the bacteria normally would never make those proteins. As thebacteria and their added genes multiplied, the bacterial colonies ineffect became tiny factories that potentially could churn out desir-able proteins in tremendous amounts.A Winning ProductThe first commercial product that Genentech made in its bacterialfactories was insulin, a protein that controls the way the body usessugar. Insulin is normally made by certain cells in the pancreas, anorgan in the abdomen that helps with digestion. Damage to thesecells results in an illness called diabetes. People with diabetes willdie unless they take insulin, usually in the form of daily injections. Insulin can be extracted in relatively large amounts from the pan-creases of slaughtered cattle and pigs, so diabetics could obtain thisvital drug fairly cheaply even before genetic engineering. Pig andcow insulin, however, are not exactly the same as human insulin,and about 5 percent of people with diabetes are allergic to these ani-mal substances. Bacteria containing the gene that produces humaninsulin make a substance essentially identical to the human form ofthe compound. Even though the percentage of diabetics who wereallergic was small, 5 percent of the 8 million diabetics in the UnitedStates amounted to enough potential customers that Boyer andSwanson believed they could make a profit. Besides, they reasoned,

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GENE SANDWICHES TO GO 31Bacteria can reproduce (by dividing) as often as once every 20 minutes. If genesfrom other organisms have been added to the bacteria, these genes will be cop-ied along with the bacteria’s own each time the microorganisms divide. In labo-ratory science, genetically engineered bacteria can be used to produce the mil-lions of copies (clones) of a DNA fragment needed to analyze the base sequencein the fragment. In the biotechnology industry, the engineered bacteria act asminiature “factories” to produce proteins specified by their added genes.

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32 Modern Genetics I WAS THERE: THE FOUNDING OF GENENTECH Herbert Boyer seemed to like casual locations for important conver- sations. The talk with Stanley Cohen that produced the pair’s famous experiments in genetic engineering took place in a delicatessen, and the chat with Robert Swanson that led to the founding of Genentech happened in a bar. In a series of interviews with Sally Smith Hughes in 1994, done as part of oral history programs conducted by the University of California at San Francisco and Berkeley, Boyer recalled the meeting with Swenson. It began in his laboratory, he said; the bar came later. He [Swanson] said he took a list of names associated with the publicity on Asilomar and went through it alphabetically, which means Paul Berg must have turned him down. I suppose I was next on the list. It was a telephone introduction. He wanted to talk, so I had him come to my lab on a Friday afternoon at quarter to five. He introduced himself, talked about what he wanted to do. . . . We spent a good deal of time that evening talking about it. Boyer had no idea how to start a company. Swanson, however, offered to provide business expertise as well as money for the ven- ture. Boyer was ready to listen. Perhaps lifting a beer mug in salute, as a sculpture in front of Genentech’s San Francisco headquarters shows, Boyer (he told Hughes) said, “Sure, why not.”if their technique could produce one protein used in medicine, itcould probably produce others equally well. Genentech produced its first genetically engineered humaninsulin in 1978, winning a close race with several other compa-nies that were pursuing the same goal. By September 1980, whenGenentech first offered its stock to the public, the federal Foodand Drug Administration (FDA) had not yet approved the newform of insulin for sale, as it must do with all new medicines.Nonetheless, investors’ excitement about the new technology was

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GENE SANDWICHES TO GO 33so great that the price of the stock rose from $35 to $89 per sharein the first few minutes of trading. James Watson writes in hishistory of DNA research, DNA: The Secret of Life, “At the time,this was the most rapid escalation in value in the history of WallStreet.” Genentech began selling recombinant human insulinthrough Eli Lilly, a huge drug company, when the FDA grantedapproval in 1982. Genetic engineers’ menu of “gene sandwiches” has grown lon-ger each year since then. The list came to include human growthhormone, given to people who would otherwise remain very shortbecause they lack the hormone, and tPA, a drug that helps dissolveblood clots after heart attacks. Vaccines that protect people againstdiseases such as hepatitis B, a serious liver disease that can leadto cancer, have also been made by genetic engineering. Genentechitself continues to make successful products, including an antican-cer drug called Avastin, which the FDA approved for limited usein 2004.Revolutionary TechnologyWhile Herbert Boyer was turning bacteria into protein factories,Stanley Cohen improved techniques for using the microbes as pho-tocopiers, producing multiple copies of genes for scientific study.Cohen has remained active at Stanford, where he is the Kwoh-TingLi Professor of Genetics as well as a professor of medicine. Boyer,by contrast, retired from UCSF in 1991 and left scientific researchbehind. The two scientists shared many awards for their work,including the Albert Lasker Basic Medical Research Award (1980),the Helmut Horten Research Award from Switzerland (1993), and theLemelson-MIT Prize for inventors (1996). Both were elected to theU.S. National Academy of Sciences and inducted into the NationalInventors Hall of Fame in 2001. Cohen received the NationalMedal of Science in 1988 and Boyer in 1990, and both received theNational Medal of Technology in 1989. In 2004, they were awardedthe Albany Medical Center Prize, a grant of $500,000—the mostmonetarily valuable prize for medicine and biomedical research inthe United States.

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34 Modern Genetics This long list of awards stresses how important the technologythat Boyer and Cohen began creating in the Hawaiian delicatessenhas become. Genetic engineering has produced life-saving medi-cines, new kinds of food, and—not least—a completely new way ofstudying genes and the way they work in the body. “Gene splicingis the most powerful and awesome skill acquired by man since thesplitting of the atom,” Time reporter Frederick Golden wrote in1981. Much later, when awarding the two scientists the Lemelson-MIT Prize, Charles M. Vest, the president of the MassachusettsInstitute of Technology (MIT), said, “Boyer and Cohen’s ingenuityhas revolutionized the way all of us live our lives.”Chronology1935 Stanley Norman Cohen born in Perth Amboy, New Jersey, on February 171936 Herbert Wayne Boyer born in Derry, Pennsylvania, on July 101960 Cohen earns M.D. degree from University of Pennsylvania School of Medicine1963 Boyer earns Ph.D. from University of Pittsburgh1965 Scientists discover that bacteria contain small, ring-shaped pieces of DNA called plasmids in addition to their main genome1966 Boyer joins faculty of University of California, San Francisco (UCSF)1968 Cohen joins faculty of Stanford University1971 Cohen devises way to make bacteria take up plasmids on demand1972 Boyer and Cohen meet during a scientiﬁc conference in Hawaii in November and plan the ﬁrst gene-splicing project1973 Paul Berg combines genes from two kinds of viruses Robert Pollack warns Berg of possible danger from Berg’s experiments, and Berg agrees to stop them

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GENE SANDWICHES TO GO 35 Boyer and Cohen combine pieces of genetic material from different types of bacteria, place the blended DNA into other bacteria, and show that the transplanted genes function Berg and 77 other molecular biologists write letter to Science, urging that the National Academy of Sciences create safety standards for recombinant DNA research1974 In July, Science publishes second letter from Berg and other scientists, in which they recommend a temporary halt to some gene-splicing experiments1975 140 molecular biologists meet in Asilomar, California, from February 24 to February 27, to work out safety guidelines for genetic engineering1976 National Institutes of Health draws up safety standards for recombinant DNA research and establishes Recombinant DNA Advisory Committee Herbert Boyer and Robert Swanson found Genentech, the ﬁrst biotechnology company1978 Genentech genetically engineers bacteria to make human insulin1980 NIH drops most safety rules for recombinant DNA experiments Genentech stock is offered to the public and sells wildly Boyer and Cohen share Albert Lasker Award for Basic Medical Research1982 Food and Drug Administration approves Genentech’s recom- binant human insulin for sale1988 Stanley Cohen receives National Medal of Science1989 Boyer and Cohen receive National Medal of Technology1990 Herbert Boyer receives National Medal of Science1991 Boyer retires from UCSF2001 Boyer and Cohen elected to National Academy of Sciences and inducted into Inventors Hall of Fame2004 Boyer and Cohen receive Albany Medical Center Prize

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36 Modern GeneticsFurther ReadingBooksShorter, Edward. The Health Century. New York: Doubleday, 1987. Chronicles the development of the National Institutes of Health (NIH) and describes some of the important research that the insti- tutes have sponsored. Includes description of NIH’s role in the devel- opment of genetic engineering and early concerns about the safety of this new technology.Watson, James D., with Andrew Berry. DNA: The Secret of Life. New York: Alfred A. Knopf, 2003. History of research on DNA and genetics in the second half of the 20th century includes chapters on the birth of genetic engineering and the development of the biotechnology industry.ArticlesBerg, Paul. “A Stanford Professor’s Career in Biochemistry, Science Politics, and the Biotechnology Industry.” Available online. URL: http://texts.cdlib.org/dynaxml/servlet/dynaXML?docId=kt1c600 1df&doc.view=entire_text. Accessed on November 12, 2004. This series of interviews with Berg, conducted by Sally Smith Hughes in 1997, is part of the UCSF Oral History Program and the Program in the History of the Biological Sciences and Biotechnology, organized by the Bancroft Library at the University of California, Berkeley. It includes discussion of Berg’s recombinant DNA research and the Asilomar conference, which Berg helped organize.———, et al. “Potential Biohazards of Recominant DNA Molecules,” Science, 26 July 1974, p. 303. Letter in which Berg, Boyer, Cohen, and others call for a temporary halt to certain types of recombinant DNA experiments.Boyer, Herbert. “Recombinant DNA Research at UCSF and Commercial Applications by Genentech.” Available online. URL: http://texts.cdlib.org/dynaxml/servlet/dynaXML?docId=kt5d5nb0 zs&doc.view=entire_text. Accessed on November 11, 2004. This series of interviews with Boyer, conducted by Sally Smith Hughes in 1994, is part of the UCSF Oral History Program and the Program in the History of the Biological Sciences and Biotechnology, organized

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GENE SANDWICHES TO GO 37 by the Bancroft Library at the University of California, Berkeley. It includes discussion of the invention of genetic engineering and the founding of Genentech.Cohen, S. N., and others. “Construction of Biologically Functional Bacterial Plasmids in Vitro,” Proceedings of the National Academy of Sciences 70 (November 1973): 3,240–3,344. Scientific paper describing the construction of the first genetically engi- neered plasmids.Golden, Frederick. “Shaping Life in the Lab,” Time, 9 March 1981, pp. 50–56. Conveys some of the excitement surrounding early commercial genetic engineering and biotechnology.Miller, Julie Ann. “Lessons from Asilomar,” Science News 127 (February 23, 1985): 122–124. Written 10 years after the conference at Asilomar, California, dur- ing which molecular biologists drew up safety guidelines for genetic engineering experiments, this article recalls the meeting and discusses its effects.Morrow, J. F., and others. “Replication and Transcription of Eukaryotic DNA in Escherichia coli,” Proceedings of the National Academy of Sciences 71 (May 1, 1974): 1,743–1,747. Scientific paper demonstrating that recombinant DNA placed in a bacterium can function in its new location.Web SitesAccess Excellence: About Biotech: Biotech Chronicles: Pioneer Profiles. Sponsored by the National Health Museum, this site for health and bioscience teachers and learners includes a history of biotechnology and biographical sketches of the industry’s pioneers. Herbert Boyer is among those profiled. http://www.accessexcel- lence.org/RC/AB/BC/Herbert_Boyer.html. Accessed on November 11, 2004.

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3 THE KILLERS INSIDE MICHAEL BISHOP, HAROLD VARMUS, AND GENES THAT CAUSE CANCERF amed British writer Robert Louis Stevenson’s The Strange Case of Dr. Jekyll and Mr. Hyde is one of the most popular mysteriesof all time. The book’s main character, physician Henry Jekyll, isrespected by all who know him—yet when Jekyll drinks a potionbrewed in his laboratory, he is transformed into a brutal killer. In1976, 90 years after Stevenson’s book was published, two scientistsin California discovered that transformations much like the onethat turned Jekyll into the evil Mr. Hyde lie behind cancer, one ofhumankind’s most feared diseases.Accidental ScientistsBefore they made their groundbreaking discovery, these tworesearchers, John Michael Bishop and Harold Eliot Varmus, wentthrough some transformations of their own. Neither had planned tobe a scientist when he was young. Bishop, born in the small townof York, Pennsylvania, on February 22, 1936, had thought aboutbecoming a musician. (Even many years later, he wrote in the auto-biographical sketch that he submitted to the Nobel Foundation that“if offered reincarnation, I would choose the career of a performingmusician with exceptional talent, preferably, in a string quartet.”)Feeling that he was not skilled enough for a career in music, however,Bishop majored in chemistry at Gettysburg College in Pennsylvania, 38